This applicationrequests support to establish the "Type 1Diabetes GeneticsConsortium". The goal of the Consortium is to organize internationalefforts to identify genes that determinean individual's risk for type 1 diabetes.A resource base of well-characterized families is proposed that will facilitatethe localization and characterizationof type 1 diabetes genes that determine disease risk. Statistical genetic analyses will determinehow these regions act in order to facilitate mapping and localization. Using the Consortium resources, members and collaborators of the Consortium will undertake positional cloning to identify individual genes that determine susceptibility or protection. Based upon current analyses of three completed genome screens, non-HLA region genes may individuallycontribute relatively small (but significant) increments in genetic risk (Xs ~ 1.12-1.30). Power analyses suggest that -4300 affected sib-pair families will be required to achieve 90% power for suggestive evidence for linkage at these levels of locus-specific risk. Current genome scan data exist on -1200 families. Over 600 affected sib-pair families have samples waiting genome scanning in other collections (United Kingdom, Finland, HBDI, Australia and Sardinia), and a request for the genome scan on these families has been submitted to CDDR. In order to meet the target of 4300 affected sib-pair families for linkage, a new collection of 2500 affected sib-pair families is required. In order to establish this combined resource of 4300 familiesand to carry out an appropriately powered search for type 1diabetes susceptibility genes, a series of specific aims are proposed to fully utilize and update existing materials and to collect new clinical resources. The specific aims of this study are to (1) newly ascertain 2500 affected sib-pair families through a European network (1200), an Australasian network (200), and a US network (1100) using standardized protocols; (2) collect, peripheral blood and establish lymphoblastoid cell lines (LCLs) to provide a renewable source of genomic DNA, RNA, protein and cells, to enable future studies of immune function; (3) genotype HLA class II and class I genes (DRB1, DQB1, DPB1, DPA1, A, B, C), INS, and CTLA4polymorphisms as recognized type 1diabetes genetic risk factors. (4) carry out disease association analyses using existing singlecase families (trios, includingan unaffected sibling when available) and cases and controls; (5) use an informativehaplotype-based map of (haplotype-tagged) SNPs to systematically and efficiently refine locations for detectingtype 1 diabetes loci. Further geneticanalyses to identify and confirm candidate genes (using haplotype-tagged SNPs) will require joint investigation by Consortium laboratories and supplemental support using Consortium material (DNA, data). The ultimate goal of this application is to provide the fundamental clinical and genetic resources to achieve the necessary sample size and sample availability for gene identification. The Consortium will establish a mechanism to ensure that scientists will work together toward a better understanding of the genetic factors that underlie risk of type 1 diabetes. The Consortium will gain a better understandingof disease mechanisms, with a purpose of altering these mechanisms and pathways in individualsat risk of type 1 diabetes.